Ipglycermides Novel potent and selective inhibitors of parasitic phosphoglycerate mutase

Ipglycermides 新型有效且选择性的寄生磷酸甘油酸变位酶抑制剂

• 批准号: 10919689
• 负责人: James Inglese
• 金额: $ 27.73万
• 依托单位: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10919689
• 关键词: Affinity; Amides; Binding; Binding Sites; Biological Assay; Boston; Caenorhabditis elegans; Categories; Cell Membrane Permeability; Cells; Chemicals; Collaborations; Cyclic Peptides; Development; Enzymes; Filarial Elephantiases; Goals; Infectious Agent; Kansas; Laboratories; Lead; Metabolic; Molecular; Mutate; Nematoda; Onchocerciasis; Organism; Orthologous Gene; Parasites; Pathogenicity; Peptide Library; Peptides; Phase; Phosphoglycerate Mutase; Publishing; Resistance; Staphylococcus aureus; Structure; Structure-Activity Relationship; System; Testing; Therapeutic; Tokyo; Work; analog; cofactor; college; design; inhibitor; insight; membrane activity; model organism; novel; phosphoglycerate; screening

This project has advanced from our Target-based Assays and Screening Strategies for Chemical Probe and Therapeutic Lead Discovery category. In continued and expanded collaboration with Prof. H. Suga (U. Tokyo), Prof. C. Hoffman (Boston College) and Scott Lovell (U. Kansas) the ADST laboratory has developed peptide macrocycles targeting this essential metabolic enzyme of the pathogenic nematode using novel cyclic peptide libraries and affinity selection and enrichment approaches. The work describing the initial phase of this project was published in 2017, and further work to elucidate the complete structure-activity relationship of ipglycermide binding to iPGM was published in 2021. This project has resulted in the discovery and characterization of Ipglycermides, the first inhibitor class that potently and selectively inhibits iPGM from all nematodes species thus far tested. We have expanded the paradigm to obtain the 1st ipglycermides capable of potently inhibiting the enzymatic activity of several prokaryotic iPGMs, including S. aureus. A model organism C. elegans systems is being developed to test the activity of membrane permeable analogs on the viability of the organism. The binding site interaction revealed from several co-crystal structures have provided general molecular insights for the design of analogs now being evaluated in across a panel of iPGM orthologs with the eventual aim to evaluate in the secondary cell and model organism assays now under development. Ipglycermide macrocyclic peptide chemotypes have now been extended to prokaryotic infectious organism iPGMs N-methyl amide containing ipglycermides, more proteolytically resistant have been generated.

该项目从我们的基于靶标的检测和筛选策略的化学探针和治疗性铅发现类别发展而来。